
Nicotine is an alkaloid found mainly in tobacco and is chemically (S)-3-(1-methyl-2-pyrrolidinyl) pyridine. Smoking of tobacco results in nicotine dependence and is habit forming. Treating nicotine dependence in order to cease smoking requires therapeutic use of nicotine. Nicotine is administered to patients through dermal patches, gums, creams, lozenges, nasal sprays or electric cigarettes to wean them away from smoking. Nicotine is also therapeutically used in treating attention deficit disorder, Tourette's syndrome, schizophrenia, Alzheimer's disease, Parkinsonism, etc.
The main source of nicotine is tobacco. Nicotine isolated from tobacco contains many related minor alkaloids as impurities in addition to impurities formed through degradation. The European Pharmacopoeia monograph on nicotine describes anatabine, anabasine, cotinine, myosmine, β-nicotyrine, nicotine-N-oxide, and nornicotine as impurities which may be present in natural nicotine. The British Pharmacopoeia also mentions anatabine, cotinine, myosmine, β-nicotyrine, and nicotine-N-oxide as impurities.
The impurities present in nicotine vary depending on the geographical source of tobacco and the season in which it is collected. It is difficult to remove these impurities since they are chemically closely related and exhibit close physical properties. On the other hand, nicotine obtained from synthetic sources should be free from impurities present in natural nicotine. Further, synthetic nicotine produced by a validated process with a well characterized impurity profile is a superior API compared to natural nicotine with its varying impurity profile.
The first synthesis of optically active (S)-nicotine was reported by Charles G. Chavdarian., et al., (J. Org. Chem. 1982, 41, 1069-1073) using N-methyl-L-prolinol.
(Scheme 1)

However, the optical purity of (S)-nicotine obtained was only 24%. The overall yield was also very poor. Stereoselective synthesis of (S)-nornicotine through reductive aminocyclization of 1,4-ketoaldehyde with pivaloyl-β-D-galactosylamine was reported by (Teck-peng., et al., Tetrahedron Letters, 1999, 40, 7847-7650) (Scheme 2). The so obtained (S)-nornicotine can be converted to (S)-nicotine by N-methylation.

In scheme 2, the nitrogen of the chiral aminosugar is utilized to build the pyrrolidine ring system. The aminosugar is not regenerated in the process for recycling making the scheme expensive. Recently another asymmetric synthesis of S-nicotine was reported involving enantioselective amination of an allylic carbonate using an expensive rhodium biphephos chiral catalyst (Pierre Dubon., et al., Synlett 2009, 9, 1413-1416).
Since the enantioselective synthesis is also too expensive, it was thought that the resolution of racemic nicotine will be more economical. Further, it is possible to racemise the unwanted R-isomer (Bowman. E. R., et al., Synthetic Communications, 1982, 12, 871-879), which makes the process attractive.
The preparation of racemic nicotine is reported in the literature (Craig. L. C, et al. J. Am. Chem. Soc., 1933, 55, 2854-2857). It can also be prepared by modifying methods reported for isotope labeled nicotine (Jones. J. P., et al., J. Am. Chem. Soc., 1993, 105, 381-387); (Hatton. W., et al., Label Compd. Radiopharm. 2009, 52, 117-122). However, these methods are not suited for the commercial manufacture of (R,S)-nicotine. The present inventors have developed a commercially viable process for synthetic (R,S)-nicotine, which is the subject matter of another patent application. Thus, an acceptable source of racemic nicotine has become available to us.
Earlier efforts for resolving (R, S)-nicotine to obtain (R)-nicotine using l-tartaric acid were unsuccessful (Barlow and Hamilton, Br. J. Pharmacol., 1965, 25, 206). Even after repeated crystallizations, optically pure (R)-nicotine could not be obtained. Several pharmacological activities reported for (R)-nicotine were based on optically impure samples (Aceto. M. D, et al., J. Med. Chem., 1979, 22, 174-177). They isolated optically pure (R)-nicotine from (R, S)-nicotine using a combination of d-tartaric acid and dip-toluoyl-l-tartaric acid. The process is laborious and time consuming. First (R, S)-nicotine was treated with d-tartaric acid in a mixture of methanol and acetone. After 2 to 5 days, four crops of mainly (R)-nicotine di-d-tartrate were obtained. Treating the salt with ammonium hydroxide followed by extraction with diethyl ether gave (R)-nicotine which still contained appreciable amounts of (S)-nicotine. It was further treated with di-p-toluoyl-l-tartaric acid in acetone and the obtained diastereomeric salt contained optically pure (R)-nicotine. The authors have not reported any method to hydrolyze the salt to obtain (R)-nicotine. Bowman et al., reported the formation of (R)-nicotine di-p-toluoyl-l-tartrate and (S)-nicotine di-p-toluoyl-d-tartrate by treating (R, S)-nicotine with the corresponding di-p-toluoyl-tartaric acid in ethanol (Bowman. E. R., et al., Synthetic Communications, 1982, 12, 871-879). However, these salts were not hydrolyzed to obtain optically pure nicotine. Thus, most of the resolution studies are for obtaining (R)-nicotine, that are mainly for scientific studies. There are no reports for obtaining the natural isomer (S)-nicotine through resolution of the racemic base.
Although not intended to be bound thereby, one objective of the present invention is to provide an efficient process for obtaining enantiomerically pure (S)-nicotine through the resolution of (R, S)-nicotine using a suitable resolving agent.
Another objective of the present invention is to obtain enantiomerically pure (R)-nicotine through the resolution of (R, S)-nicotine using a suitable resolving agent.
Another objective is to develop a process for recovering the resolving agent without affecting its chemical chiral purity.
Yet another objective is to demonstrate a suitable racemization process for (R)-nicotine so that the whole process is commercially viable.